De-ubiquitinase DUB3 binds to BRD4, but not BRD2/3, via a specific C-terminal motif (CTM), antagonizes SPOP-mediated BRD4 ubiquitination, and promotes BRD4 de-ubiquitination and stabilization, leading to BET-BD inhibitor resistance in cancer cells (Jin et al., 2018). The gene discussed is SPOP; the disease is cancer.